Background: Heparins are used for circuit anticoagulation during continuous renal replacement therapy (CRRT). Because heparins cause systemic anticoagulation, they increase the risk of bleeding. Citrate provides regional anticoagulation. Since citrate is a buffer as well, its use has metabolic consequences. The preferential use of citrate therefore remains controversial. Methods: A synthesis was performed of published studies comparing citrate to heparin for anticoagulation in CRRT with specific regard to feasibility, efficacy and safety. Search of the literature was made to explain the reported superiority of citrate. Results: Citrate provides good metabolic control if and when a well-designed protocol is strictly followed. Randomized studies report similar or longer circuit survival with citrate compared to heparin and less bleeding. The largest randomized trial up to now found that citrate was better tolerated than heparin and improved patient and kidney survival, especially in patients after surgery, with sepsis, a high degree of organ failure or younger age. Both citrate and heparin interfere with inflammation. Conclusion: During critical illness, regional anticoagulation with citrate for CRRT seems superior to heparin anticoagulation concerning tolerance and safety, mainly due to less bleeding. Whether circuit survival is better depends on the modality. In addition, citrate seems to improve patient and kidney survival. This finding needs to be confirmed. Citrate seems to confer a specific benefit in severe organ failure and sepsis. To what extent citrate protects or heparin does harm in the setting of multiple organ failure needs to be unraveled.